day 5 - A practical approach to the bleeding patient Flashcards
Specific symptoms may indicate the type of the bleeding disorder:
- Superficial bruising, skin purpura and bleeding from mucosal surfaces such as the mouth are more indicative of a platelet disorder.
- Deep muscular haematomas and haemarthroses (bleeding into joints) are suggestive of a disorder of coagulation factors.
whats a platelet
Platelets are anuclear fragments derived from the cytoplasm of megakaryocytes. Megakaryocytes are giant, multinuclear cells and are by far, the largest cells found in normal bone marrow. Platelets are the smallest cellular element of peripheral blood and their normal lifespan in the circulation is 7 days. They are discus shaped, with a membrane containing surface openings which connect with a canalicular system. Two types of granules can be identified; dense granules (which are rich in the nucleotides ADP and ATP), and alpha granules (which contain coagulation factors such as fibrinogen, factor V, vWF, and PA1-1). The canalicular system enables the rapid delivery of granule contents to the platelet surface after activation. The platelet membrane expresses glycoproteins that provide binding sites for circulating and tissue-bound proteins that are critical for normal haemostasis.
Tests of Platelet Numbers/Function
Platelets may be counted in whole, anticoagulated blood using automated particle counters. This normally forms part of the full blood count (FBC). A reasonable assessment for clinical purposes may be made by examination of a stained blood film. A low platelet count may be due to decreased production from the bone marrow (e.g. due to infiltration with leukaemia), or increased destruction. Increased destruction can be due to auto-immune destruction by the reticulo-endothelial system or consumption by an uncontrolled clotting process as part of disseminated intravascular coagulation.
Platelet aggregometry is now the main method of testing platelet function. In this test agents that activate platelets, such as ADP or collagen, are added to a suspension of platelets in plasma causing them to aggregate. As they do so the plasma becomes clearer. Light transmittance through the solution can be measured to provide a quantitative measure of platelet aggregation. Similar assays can be done in whole blood by measuring changes in impedance that occur after platelet aggregation.
what is thrombocytopenia
The terms thrombocytopenia and thrombopenia refer to a disorder in which there is a relative decrease of thrombocytes, commonly known as platelets, present in the blood.
Normal Platelet count:
Normal Platelet count: 150-400 x 109/L. The following levels may be used as a guide:
80 x 109/L: sufficient for most minor procedures
>100 x 109/L: sufficient for most major surgery
underproduction causes of thrombocytopenia
Underproduction
The main causes are either:
(a) infiltration of the bone marrow e.g. leukaemia or secondary malignancy.
or:
(b) Reduction in the numbers of megakaryocytes or abnormal megakaryocyte differentiation e.g. aplastic anaemia, severe megaloblastic anaemia, excess alcohol intake.
Diagnosis of these conditions requires a bone marrow aspirate and/or biopsy. It is an essential test if marrow pathology is suspected, but is not always necessary if peripheral destruction is the likely cause.
Peripheral Destruction/consumption causes of thrombocytopenia
If the bone marrow shows normal or increased megakaryocytes, this suggests that increased peripheral consumption or destruction of platelets is the cause of the low count.

Increased peripheral platelet destruction. This is usually immunological in nature and due to antibodies adhering to platelets and causing their premature removal in the reticulo-endothelial system (predominantly the spleen). The commonest cause is idiopathic or immune thrombocytopenic purpura (ITP). In some cases ITP may be part of a wider disorder such as SLE or lymphoid malignancies (especially B-cell chronic lymphocytic leukaemia). It may also be caused by numerous drugs (e.g. quinine, rifampicin and heparin) where antibodies made against the drug are absorbed onto the platelet surface membrane. These immunological disorders can be diagnosed by the demonstration of platelet associated immunoglobulin - antibodies bound to platelet surface antigens. This is a difficult test and restricted to specialist laboratories, therefore it is rarely used in the diagnosis of ITP.
Increased platelet consumption. This occurs when platelets are consumed in their normal physiological role of haemostasis. Classically it is a feature of disseminated intravascular coagulation (DIC) where thrombocytopenia is associated with consumption of all clotting factors, prolongation of clotting times and a microangiopathic haemolytic anaemia due to the chopping up of red blood cells by fibrin strands.
Pooling. Approximately a third of circulating platelets are situated in the normal size spleen. In patients with moderate or severe splenomegaly, this proportion can increase appreciably resulting in a circulating thrombocytopenia. Splenomegaly is a feature of many disorders such as myelofibrosis, portal hypertension, malignancy and leishmaniasis.
Massive transfusion. Stored banked blood contains no functional platelets. Besides diluting the platelets in the patient’s circulation it contains clumps of dead white cells and platelets. These microaggregates are sticky and the patient’s platelets may adhere to them before they are filtered out of the circulation in the reticulo-endothelial system. This can be partly prevented by using a special microaggregate filter in the giving set. In addition the patient is often consuming platelets at the site of bleeding or operation wound.
If the platelet count is normal but the history is of platelet-type bleeding (e.g. purpura or bleeding from mucosal surfaces), what should you consider?
If the platelet count is normal but the history is of platelet-type bleeding (e.g. purpura or bleeding from mucosal surfaces), an abnormality of platelet function should be considered.
The history is very important. Concentrate on the age at which bleeding symptoms were first noticed and ask specifically if other family members have similar symptoms. This will provide an early indication as to whether the disorder is congenital or acquired. An accurate family tree is essential for deciding the pattern of inheritance in congenital bleeding disorders.
Acquired abnormalities of platelet function:
a) Drugs. The list of drugs affecting platelet function is very long. Aspirin and other non- steroidal anti-inflammatory agents are very powerful inhibitors of platelet function and the most common culprits. They are available without prescription. Herbal remedies and other dietary supplements such as fish oils may also affect platelet function and cause clinically significant symptoms. Ideally all medication should be stopped for a two week period before platelet function studies are performed.
b) Secondary. In association with a variety of conditions including chronic renal failure, myeloproliferative disease, myelodysplasia and glycogen storage disorders.
Congenital abnormalities of platelet function:
These are rare inherited conditions that may be classified as follows:
a) Membrane glycoprotein (Gp) abnormalities. The commonest are Bernard-Soulier syndrome (deficiency of Gp Ib/IX) and Glanzmann’s thrombasthenia (deficiency of Gp IIb/IIIa).
b) Defects in enzyme pathways. Generally involving enzymes in the pathway of arachidonic acid metabolism such as cycloxygenase.
c) Storage Pool Disorder. Classically caused by a reduction in dense granules leading to a reduction in release of platelet nucleotides and therefore impaired activation. It may be part of a wider syndrome such as Hermansky-Pudlak or Chediak-Higashi.
To further investigate platelet function defects, the following tests should be considered:
i. Platelet aggregometry.
ii. Measurement of platelet nucleotides and their release following aggregation
iii. Quantification of specific membrane protein receptors particularly Gp Ib/IX and Gp IIb/IIIa. This is now readily done by flow cytometry using specific fluorescent labelled monoclonal antibodies against these antigens.
iv. Investigation of the arachidonic acid pathway and calcium flux.
v. The exclusion of immunological destruction depends on specific assays for platelet
associated immunoglobulins.
Treatment of platelet function problems
- Obviously stop the offending drug or treat the associated disorder if possible.
- For congenital defects there is no cure and treatment is generally restricted to cover of predictable bleeding episodes (e.g. surgery) or episodes of clinically significant haemorrhage. The options are:
Platelet transfusions
Desmopressin (DDAVP) which may improve platelet function in some cases Anti-fibrinolytics (e.g. tranexamic acid) which have no effect on platelet function but
improve clot stability. - For ITP the following treatment options should be considered:
Immunosuppressants (e.g. prednisolone) to reduce the amount of anti-platelet
antibody and inhibit splenic sequestration.
Splenectomy to remove the major site of platelet destruction.
Infusion of high doses of intravenous human gammaglobulin, which may work by
inducing a state of temporary reticulo-endothelial blockade.
Approximately 60-70% of patients with ITP will enter remission following steroids or splenectomy. Some patients with chronic ITP fail to respond to splenectomy or continual low dose steroids. These patients are very difficult to manage and one should consider other immunosuppressive agents (e.g. rituximab or azathioprine).
what is Thrombocytosis
Thrombocytosis (or thrombocythemia) is the presence of high platelet counts in the blood, and can be either primary (also termed essential and caused by a myeloproliferative disease) or reactive (also termed secondary). Although often symptomless (particularly when it is a secondary reaction), it can predispose to thrombosis in some patients.
causes of thrombocytosis
Indicated by a platelet count above the normal range. This is most commonly reactive to some inflammatory or malignant process but may be caused by a primary marrow disorder.
i. Reactive causes. Infection, chronic bleeding, iron deficiency (even when due to dietary deficiency), trauma, malignancy and inflammatory disorders such as connective tissue disease. In reactive thrombocytosis the platelet count is rarely over 1000 x 109/L.
ii. Primary. One of the myeloproliferative disorders most commonly Essential Thrombocythaemia (ET). Approximately 25% will have bleeding symptoms with abnormal platelet function and 25% may develop vascular thromboses. i.e. they may suffer from both thrombotic and bleeding problems. These improve when the platelet count is brought down to normal levels by cytotoxic agents such as hydroxyurea or anagrelide.
overview of the waterfall hypothesis of coagulation
The purpose of the coagulation cascade is to produce a large burst of thrombin. This enzyme converts fibrinogen to fibrin which forms an insoluble clot. The reactions forming the cascade are shown in the revised waterfall hypothesis below. Damage to a blood vessel results in circulating factor VII (FVII) coming into contact with extravascular tissue factor (TF). A small amount of thrombin is produced during this initiating phase before the initiating TF-FVIII complex is shut down by tissue factor pathway inhibitor (TFPI). Although this small amount of thrombin does not produce much fibrin it stimulates the amplification loop consisting of factors XI, IX, VIII, X and V. This self-propagating system allows a large burst of thrombin to form a fibrin clot. Once the fibrin clot has formed factor XIII stabilises it by cross-linking the fibrin strands.
After the amplification loop is activated thrombin switches from a pro-coagulant to an anti- coagulant function. This leads to activation of the anti-coagulant protein C pathway which inhibits the amplification loop by inactivating factors V and VIII. The main inhibitors of coagulation are the protein C pathway, antithrombin and TFPI. These are important in preventing unwanted spread of the coagulation cascade. Deficiencies of the coagulation factors lead to bleeding symptoms while deficiencies of the anticoagulant factors predispose to thrombosis.
