Background
Based on the thrombotic potential, the processes in human body can be classified into prothrombotic and antithrombotic processes.
The prothrombotic processes are needed to prevent leakage of blood from the vasculature outside (bleeding) after its disruption.
The antithrombotic processes are needed to prevent blood form getting clotted inside intact vasculature.
Prothrombotic process
The process consist of the tissue factor and vWF from the subendothelial layer; phospholipids from the platelets, erythrocytes and activated endothelium; activated platelets; coagulation factors and antifibrinolytic system (which prevents the fibrin degradation).
Activated endothelium and pro-inflammatory state is an important component of prothrombotic process.
Inflammation, endothelial dysfunction, thrombocytosis, increased tissue factor, coagulation factors and vWF leads to prothrombotic state.
Arterial bed is a high flow bed and the thrombosis takes place with platelet activation and aggregation secondary to exposure to collagen and vWF from subendothelial system.
Venous bed is a low flow bed, in which thrombosis usually takes place due to stasis and abnormalities of coagulation (usually decreased anticoagulants).
Antithrombotic process
Antithrombotic process is mediated primarily by the intact endothelium with anticoagulants, circulatory anticoagulants (Protein C/S complex and anti-thrombin), fibrinolytic mechanism, and pathological inhibitors against coagulation factors, platelet receptors and vWF.
Decreased platelets, decreased platelet functions, decreased coagulation factor activity/content, increased anticoagulants, circulating inhibitors against coagulation factors, vWF and platelet receptors are important causes for antithrombosis.
Antithrombosis leads to bleeding. Altered vessel wall integrity is an important component for bleeding.
Discrepancy between different indicators of pro/anti-thrombotic process
When there is discrepancy between different indicators, diagnostic and therapeutic dilemma occurs as to the predominant process (pro or anti-thrombotic).
The following are the situations when there is discrepancy
Syndrome of Endothelial Dysfunction (Thrombocytopenia and Thrombosis)
Whenever there is endothelial dysfunction, there is activation and aggregation of platelets leading to thrombocytopenia. The process of endothelial dysfunction leads to activation of pro-inflammatory and pro-thrombotic signals leading to thrombosis.
Ths above syndrome leads to the formation of Thrombotic Microangipathy which lead to microangiopathic hemolytic anemia, thrombocytopenia and thrombosis.
The thrombocytopenia in this setting is usually mild to moderate (usually 30000 - 100000/cu mm), except in DIC where it can be less than 20000/cu mm also.
Thrombocytopenia is usually not treated as it is a reactionary process.
Other than bleeding variety of DIC, the other varieties are prothrombotic and platelet transfusion is usually contraindicated and there is role of anti coagulation in the management of the disease.
The important clinical situations in which above process occur are
Disseminated Intravascular Coagulation: The endothelial dysfunction takes place due to excess tissue factor released in blood stream leading to the consumption of coagulation factors and platelets. In the milder form of DIC, which occurs early in course and is compensated, the excess activation of coagulation factors and platelets can lead to both macrovascular and microvascular thrombosis. In the full blown form of DIC, the body is not able to compensate for the loss of coagulation factors, which lead to a global decrease in coagulation factors and bleeding ensues.
Thrombotic Thrombocytopenic Purpura: This syndrome complex is characterised by platelet plug formation due to decreased ADAMTS 13
levels leading to failure of the ultralarge polymers of vWF to be cleaved. It leads to excessive platelet activation and endothelial dysfunction. Decreased ADAMTS 13 levels can be due to decreased production (hereditary) or due to antibody mediated increased clearance. It is characterised clinically by fever, renal failure, neurological dysfunction and normal coagulation parameters. Thrombosis usually occurs in microcirculation and arterial bed. Plasmapharesis and plasma exchange with the aim to replace normal ADAMTS 13 and remove antibodies forms the mainstay of treatment. Platelets transfusions are contraindicated as they precipitate more platelet plug formation.Heparin Induced Thrombocytopenia and Thrombosis: This syndrome is characterised by activating antibody formation against the platelet factor 4 - heparin complex after exposure to heparin. The antibody leads to platelets and endothelial activation. Clinically, it is characterised by thrombocytopenia and thrombotic manifestation (venous and arterial). Chances of development of the antibody is proportional to the molecular weight of heparin (increased with higher molecular weight heparin). The mainstay of treatment is withdrawal of heparin and replacement with other parenteral anticoagulants.
Antiphospholipid Syndrome: APS is characterised by the antibodies against antiphospholipids (which are present over platelets and endothelial cells), which lead to prothrombotic state with thrombocytopenia. The prothrombin time may be fallaciously increased due to in vitro affect of antiphospholid antibodies in conduct of the tests.
Syndrome of acquired vWF deficiency
Thrombocytosis due to any reason is associated with increased incidence of arterial thrombosis. Excess circulating platelets lead to increased usage of vWF and it can lead to decreased circulating vWF. Paradoxically at platelets counts more than 1000000/cu mm, chances of bleeding can be more.
Antiplatelets should be used with caution till the time platelets are reduced to less than 1000000/cu mm.
Managing patients with bleeding and thrombosis
As a general rule, antiplatelets and anticoagulants are not given for patients with thrombosis (arterial or venous) if they have predominant anticoagulation milieu, like active bleeding, platelets less than 50000/cu mm and/or deranged coagulation parameters. In case of life threatening thrombosis, anticoagulants and antiplatelets can be started after correcting the anticoagulation milieu.
Conclusion
The above write up deals with situations where there is discrepancy between various indicators of pro and anticoagulation. Managing such cases need high degree of clinical suspicion, delicate decision making and individualised treatment for achieving optimal outcome.