Bleeding complications: therapeutic strategies in haemostasis


  • Conflicts of interest: To be confirmed.

  • 4D-S27-01

Prof. Dr. med. Michael Spannagl, Klinikum der Universität München, Max-Lebsche-Platz 32, D-81377 München, Germany


Several haemostyptic agents as well as cellular and plasmatic blood products are available for treatment of bleeding complications. Selective application of these compounds according to the patient’s haemostatic disturbances is superior to standard application of cellular concentrates and fresh frozen plasma. Near-patient testing of whole blood coagulation and fibrinolysis has been suggested for goal directed therapy. Recent data show reduction of consumption of blood products using algorithms and tailored therapy.


Unexpected coagulopathies still remain as a diagnostic and therapeutic challenge. Risk factors and reasons behind unexplained bleeding are heterogeneous and multifactorial. Bleeding most frequently occurs during and after surgical intervention or trauma, i.e. in situations where trauma and secondary alterations (e.g. haemodilution) are added to the disposition of the patient. Furthermore, it must not be forgotten that uncontrolled surgical bleeding may also lead to a coagulation disorder sooner or later because of the increasing loss of clotting factors and blood cells. Prediction and, if necessary, management of acute bleeding are of general interest. During such complex haemostasis disorders, near-patient testing and treatment algorithms have been added to blind therapy and needs further validation.

Bleeding complications present daily in clinical routine associated with interventional procedures. This is not just because of the more frequent clinical use of old and new substances with anticoagulant effects (platelet-, coagulation-inhibitors) but also because indications for the transfusion of fresh frozen plasma (FFP) and platelet concentrate (PC) are being questioned more closely [1]. This is not just on medical grounds – because of the not inconsiderable adverse effects [2–4] – but also for reasons of economics [5].

Several blood components and haemostyptic agents are available for management of acute bleeding. Inappropriate polytherapy, however, is not acceptable and should be avoided. In most cases only the right medication in the appropriate dose helps the patients. This leads to a general interest in improvement of the diagnostic and therapeutic approach to actively bleeding patients. Some debate exists about suitable methods, which reflects haemostasis during these complex processes. In particular, near-patient testing is used more and more. Before discussing concepts for diagnosis and management of acute bleeding, it has to be substantiated that surgical bleeding as a major reason of perioperative and periinterventional bleeding must involve the surgeon or interventionalist in the management process (Table 1).

Table 1.   Bleeding as major cause of complicated patient history
Enhances transfusion requirements
 Risk of infection
 Other risks
Prolongs surgery or intervention
 Enhances costs
 Prolongs anaesthesia
 Impairs outcome
Causes re-explorations
 Prolongs ICU stay
 Enhances costs
 Limits outcome
 Makes the intervention more difficult
 Poor visibility of the interventional field

Periinterventional bleeding and outcome

Perioperative and periinterventional bleeding are related to patient outcome. This has been shown in several surgical and interventional disciplines. Large multicentre studies have shown that postoperative bleeding is an independent risk factor for morbidity and mortality after cardiac surgery, especially when re-operation is needed to achieve haemostasis [6,7]. Furthermore, the number of packed red-blood-cell units that are regularly infused because of severe surgically induced bleeding is an independent risk factor for mortality in hospital [8] and in long term [9] after a cardiac operation. The higher morbidity risk from bleeding after cardiac operations is associated with a longer postoperative hospital stay [6] and much higher treatment costs. The significantly increased mortality risk in particular requires safe and effective preventive measures, including surgical arrest of bleeding and differentiated haemostatic treatment with blood products and coagulation factors.

Also, in interventional cardiology and radiology bleeding is associated with poor outcome. Non-modifiable (age, gender, weight, renal insufficiency, anaemia) and modifiable risk factors (antithrombotic therapy, PCI procedure characteristics) have been identified [10].

In general, the traditional attitude of the surgeon to prefer bleeding (which can easily be substituted by blood components) vs thromboembolism (which can hardly be detected) is in debate more and more.

Prediction of bleeding complications

The predictivity of the routine coagulation parameters PT, aPTT and platelet count in interventional medicine is rather weak. From a clinicians view the acute clinical signs as well as any information concerning own or family history of bleeding or thromboembolic events are of utmost importance.

Is the patient at increased risk of bleeding because of a congenital or acquired (e.g. through medication) coagulation disorder?

This question should, of course, be dealt with in the preoperative phase. Careful consideration of clinical signs as well as comprehensive information on comorbidity and comedication and anamnestic information is necessary. The value of standardized coagulation history has been shown of great value in this respect. If there is a positive history, further investigation by a specialized haemostasis laboratory should be carried out and, if necessary, specific coagulation management prescribed in advance. In most patients suffering from hereditary bleeding disorders approved therapeutic algorithms can be applied. Except from very rare deficiencies, plasma concentrates or recombinant factors are available for replacement therapy.

Knowledge of antiplatelet and/or anticoagulant medication of the patient is of utmost importance. Tailored recommendation for improvement of platelet function (DDAVP, platelet concentrate) or antagonization of vitamin K antagonist effects (PPSB) or heparin antagonization (protamin) are available.

Causes of haemostasis disorders

Haemostasis disorders can have several causes (Figs 1 and 2). In most clinical cases acute bleeding is a multifactorial process involving several components of plasmatic and/or cellular haemostasis. Chronic diseases, such as comorbidities of the haemostasis-related organs (liver – kidney – bone marrow) and hereditary diseases, can be differentiated from more acute alterations because of trauma, inflammation, haemodilution and the current treatment. The resulting alterations affect the plasmatic coagulation factors, platelets and the fibrinolytic system. In this context, own and family history of bleeding complications are of major impact. In a registry of patients with chronic subdural haematoma anticoagulants, antiplatelets, haematologic/neoplastic disease and ethylism were identified as major risk factors [11].

Figure 1.

 Surgical intervention as the trigger for acute bleeding.

Figure 2.

 Multifactorial cause for acute bleeding.

Bleeding most frequently occurs during and after surgical interventions or traumas, i.e. in situations where trauma and secondary alterations (e.g. attributed to haemodilution) are added to the disposition of the patient. During such complex haemostasis disorders the predictivity of the routine parameters PT, aPTT and platelet count is rather weak. This led to the interest in laboratory methods, which better reflect haemostasis during these complex processes (Fig. 3).

Figure 3.

 Comedication and comorbidity.

The majority of coagulation defects that present intraoperatively and acutely as the result of massive haemorrhage in patients without relevant primary disease are caused by loss, consumption and dilution of blood and come under the heading of dilution coagulopathies. In all these cases, the results of routine tests, prothrombin time (PT) and activated partial thromboplastin time (aPTT) are pathological at an early stage. Specific consequences, however, cannot be derived from the laboratory results.

Although these altered laboratory tests are also indicative of disseminated intravascular coagulation (DIC), the pathogenesis is different. In trauma and in perioperative blood loss we find a consumption coagulopathy exacerbated by volume replacement, loss and possible acidosis and hypothermia and other metabolic disturbances, not primarily induced by coagulation activating substances like in classical DIC.

The rationale for coagulation management in acute bleeding has to be based on the understanding of the pathophysiological processes.

As distinct from a surgical problem, a disorder of haemostasis cannot often be seen directly, so that a picture has to be built up indirectly from the test results, and any clinical and anamnestic pathology. Finally, rare bleeding disorders should also be mentioned in this context. Inherited rare bleeding disorders because of single factor or platelet glycoprotein receptor deficiencies may be of importance especially if the haemostatic system is altered by trauma or operation.

The development of acquired antibodies to clotting factors is a typical postoperative complication. Recognition of these patients with rapidly developing bleeding signs and prolonged aPTT is still a major challenge. Despite increasing awareness for acquired inhibitors as a cause of acute bleeding, bad outcome often occurs especially in elderly patients [12]. Recombinant rVIIa or Feiba have been applied successfully for management of acute bleeding in acquired haemophilia [13].

Coagulation tests – from the lab to the patient

Looking at haemostasis from an analytical point of view, it makes sense to divide the clotting process into four phases: primary haemostasis (Platelet–Vessel wall-, Platelet–Platelet-Interaction) thrombin generation (Clotting Time) clot formation Dynamics of (Clot Formation, Clot Firmness) clot breakdown (Hyperfibrinolysis).

Primary haemostasis

Coagulation has been recognized as a cell-based system. Therefore, coagulation diagnostic in whole blood is of major importance. Besides thromboelastography, whole blood platelet aggregometry is available for near-patient testing. Test systems measuring under high shear stress conditions have also been introduced. The PFA-100® System is applied for preinterventional screening for disturbances of primary haemostasis [14]. Because of a significant impact of red cell and platelet concentration, PFA measurement during acute blood loss is not recommended. Aggregometry methods can be applied for the detection of antiplatelets.

Thrombin generation

Conventional coagulation tests (e.g. prothrombin time, PT; activated partial thromboplastin time, aPTT) determine the thrombin generation phase until formation of the first fibrin fibres. In addition, these conventional coagulation parameters are primarily intended to detect substances acting on coagulation (heparin, vitamin K antagonists) or reduced activity of particular clotting factors as sensitively as possible. As citrated plasma is generally used for modern clotting tests, any effects of cellular elements such as platelets, leucocytes and red-blood-cells are lacking.

Therefore, it is no surprise that these tests mostly fail in diagnosing acute intraoperative and postoperative bleeding [15] so that alternative analytical procedures and supplementary diagnostic methods are being looked for in this context.

Problems of classical coagulation tests with perioperative coagulation disorders

  • • No detection of hyperfibrinolysis
  • • False high fibrinogen measurement in the presence of colloids (like HES or gelatine) fibrin(ogen) split products and heparin (avoid derived fibrinogen measurement) heavily elevated FDP’s.
  • • False long PT and aPTT in case of hypofibrinogenaemia and afibrinogenaemia,
  • • Platelet count does not implicate function
  • • Clotting times (e.g. PT, aPTT and TT) only determine the speed of thrombin generation, but not the mechanical stability of the clot
  • • Results of coagulation tests performed in a central laboratory are usually not available before the next 30–60 min in the operating theatre (Fig. 4).
Figure 4.

 Choice of laboratory tests.

Clot formation

Dynamics and maximum extent of clot formation can only be calculated using viscoelastic methods. Thromboelastography is extensively used in perioperative and trauma bleeding. Standard procedures applying cellular and plasmatic blood products guided by results of thromboelastography results have been implemented. Several data show significant cost reduction [16,17], although the additional implementation of therapeutic algorithms together with near-patient testing may have a significant impact.


As a general phenomenon during serious medical conditions hyperfibrinolysis is much more common than previously assumed. It occurs in major trauma, hepatic trauma, severe pelvic and brain injury. The current diagnostic deficiency to early identify hyperfibrinolysis can be explained by the absence of routine laboratory tests for fibrinolysis. The most efficient diagnostic tool to detect hyperfibrinolysis is thromboelastography. Recent studies have shown that approximately 15–20% of major trauma patients suffering from massive bleeding also present with pronounced hyperfibrinolysis. This could be supported by hypothesis that early administration of antifibrinolytic agents may be beneficial during haemorrhage control in severe bleeding patients.

Most of the above-mentioned test systems can be applied in a near-patient setting as a point of care testing. A major advantage of this approach is to provide coagulation results in a clinically relevant time frame. As a consequence, automatic ordering of blood products is prevented for severely bleeding patients. By using electronic data transfer, such coagulation machine can also be used in a central lab facility, if a short turn around time is provided. Regarding the right choice of the test system, it is important to identify questions derived from clinical need and to find out suitable machines (Fig. 5).

Figure 5.

 Bleeding: therapeutic options.

Targeted treatment of bleeding events

The best approach to the bleeding patient is to identify and restore the haemostastic defect (Fig. 6). Therapy of choice is a targeted application of haemostyptic drugs, cellular concentrates or factor concentrates. Traumatic or perioperative bleeding is usually multifactorial and subject to the dynamics of the event. Besides the effects of medications (e.g. heparin) and the loss and consumption of clotting factors, there often is a disorder of the cellular elements (e.g. platelets) to be taken into consideration. Dilution of cellular and plasmatic haemostatic compounds is always a concern in acute bleeding. Therefore, early and high-dose FFP application is recommended [18,19]. Recent discussions suggest 1:1 replacement in acute bleeding [20].

Figure 6.

 Tailored haemostatic therapy.

During bleeding a multitude of different therapeutic options is at disposition to the physician. The difficulty is to choose the right medication at the right time and to evaluate, how much respectively and how often the respective therapeutic option has to be applied. Typically, only the right therapy will stop the bleeding. It will hardly be of any use to the patient, if he is transfused with FFP while he is bleeding because of a thrombocytopenia or a hyperfibrinolysis. Although this sounds self-evident, in the clinical common routine a “blind” therapy is often applied. This means that different medication and blood products are administered consecutively until the bleeding stops. If the cause of the bleeding is not the most obvious, unnecessary medication and blood products are administered. Thus, unnecessary costs are created, and the patient is exposed to potentially harmful agents.

Tailored Therapy
DDAVPPrimary haemostasis (Willebrand-factor release, platelet activation)
Willebrand-factor concentratePlatelet adhesion
Coagulation factor concentrates, rVIIaThrombin Generation
FibrinogenFibrin Formation
Erythrocyte/Platelet concentrateThrombus Formation
Tranexamic AcidAntifibrinolytic