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Competing Interests: Disclosure The authors report no conflicts of interest in this work.

Thrombocytopenia is a frequent phenomenon in intensive care medicine. A variety of conditions can be responsible for low platelet counts. As platelets are part of the primary hemostatic system, bleeding is the most important complication of thrombocytopenia. Proper workup of the differential diagnosis to identify the cause of thrombocytopenia is essential because the various underlying disorders require different diagnostic and therapeutic management strategies. A low platelet count is a strong predictor of outcome in critically ill patients.This article summarizes the differential diagnosis and diagnostic workup of thrombocytopenia in the critically ill, describes the most important conditions, and gives an overview on therapeutic options and strategies.

Congenital disorders of platelet function are a heterogeneous group of disorders that are often not detected until bleeding occurs. In clinical settings only a few methods have proven to be useful for identification and classification of inherited platelet disorders. For a rational diagnostic approach, a stepwise algorithm is recommended. Patient history and clinical investigation are mandatory. Von Willebrand disease and other coagulation disorders should always be ruled out prior to specific platelet testing. Platelet count, size, volume (MPV) and morphology may guide further investigations. The PFA-100® CT is suited for screening for severe platelet defects. Platelet aggregometry allows assessment of multiple aspects of platelet function. Flow cytometry enables diagnosis of thrombasthenia Glanzmann, Bernard-Soulier syndrome and storage pool defects. Molecular genetics may confirm a putative diagnosis or pave the way for identifying new defects. We present an unabridged version of the interdisciplinary guideline.

Inherited disorders of platelet function are a heterogeneous group. For optimal prevention and management of bleeding, classification and diagnosis of the underlying defect are highly recommended. An interdisciplinary guideline for a diagnostic approach has been published (AWMF # 086-003 S2K; Hämostaseologie 2014; 34: 201-212). Underlying platelet disorder, platelet count, age and clinical situation modify treatment. Exclusive transfusion of platelet concentrates may be inappropriate as potentially adverse effects can outweigh its benefit. A stepwise and individually adjusted approach for restitution and maintenance of haemostasis is recommended. Administration of antifibrinolytics is generally endorsed, but is of particular use in Quebec disease. Restricted to older children, desmopressin is favourable in storage pool disease and unclassified platelet disorders. Although licensed only for patients with Glanzmann thrombasthenia and alloantibodies, in clinical practice rFVIIa is widely used in inherited platelet disorders with severe bleeding tendency. This guideline aims at presenting the best available advice for the management of patients with inherited platelet function disorders.

Both for diagnosis of congenital and acquired platelet dysfunction as well as for therapy monitoring after application of platelet function inhibitors various methods have been established for evaluation of platelet function. In contrast to the gold standard of platelet function testing, the light transmission aggregometry in platelet rich plasma the Point-of-care (POC) analyzers allow fast analysis of platelet function without extensive laboratory work up. The conditions of the pre-analytical phase, however, are still of enormous importance in the prevention of medical errors. There is increasing clinical data in monitoring the effect of platelet aggregation inhibitors, showing that quantitative determination of the platelet function degree correlates with risk of increased bleeding or stent thrombosis. However, it is still unclear, which is the optimal test system, to predict the clinical outcome of these patients.

Inherited thrombocytopathies are much less frequent in comparison to acquired platelet function disorders. However, congenital disorders can lead to severe bleeding tendency and are often not diagnosed. They are induced by different platelet defects based on disorders of platelet adhesion, receptors, secretion and signal transduction. In some cases they are associated with thrombocytopenia, giant platelets and various comorbidities. This article gives an overview regarding diverse defects, their diagnosis and treatment options.

Numerous laboratory tests are in use to detect congenital or acquired platelet function disorders. Platelet aggregometry, using ADP, collagen, arachidonic acid or ristocetin as inductor is the standard test system for diagnosis. It is also used to detect platelet non-response to antiplatelet therapy. Studies have demonstrated that laboratory assessment of platelet non response to aspirin or clopidogrel is associated with adverse outcomes, and they indicate the importance of adjusting antiplatelet therapy in patients with a low degree of platelet inhibition. Nevertheless, a standardized method for identifying these patients is still missing.

Unlabelled: The Aspirin-like defect (ALD) is caused by defects in the intraplatelet arachidonic acid (AA)-metabolism. We here present the characteristics of a larger cohort in a single centre., Patients, Methods: Based on 17 ALD index patients bleeding symptoms, agonist-induced platelet aggregation and closure times in the PFA-100 test were analysed in a family cohort of altogether 52 individuals from 17 families. Absent aggregation to AA (maximal aggregation or=1 bleeding symptoms., Conclusion: In case of a bleeding tendency diagnostic procedures should rule out primary haemostatic defects. Hereditary platelet function defects including ALD are an important differential diagnosis. Family studies are reasonable.

Platelet disorders frequently represent a cause of bleeding disorders with a late manifestation and spontaneous bleeding. Disturbances of cellular hemostasis can be of quantitative nature due to an altered production or destruction of platelets. Qualitative disturbances can be associated with defects of adhesion, secretion or degranulation. Drug induced reactions, inflammatory processes and autoimmune reactions are the most frequent underlying disorders. Even a late manifestation, however, does not exclude congenital disorders. In the differential diagnosis of thrombocyte disorders the anamnestic analysis of the clinical circumstances of manifestation, of a family background and potentially interfering drugs are of central importance. Template bleeding time, aggregometry and flow cytometry are complementary methods for the characterization of functional defects. First of all, a von Willebrand syndrome as the most frequent congenital form of a mucocutaneous bleeding pattern needs to be excluded. The clinical context is very important in the analysis of disturbances of platelet turnover. Reticulated platelets allow the quantitative assessment of reduced production or increased destruction. Platelet indices, morphological assessment of blood and bone marrow and immunological tests allow the pathogenetical classification of thrombocytopenia. Idiopathic thrombocytopenia (ITP) is a frequent diagnosis by exclusion. The analysis of glycoprotein expression and the genetic characterization of suspected congenital defects are only performed in selected cases. Clinical and laboratory assessment are complementary in the discrimination of secondary forms of thrombosis from clinically relevant clonal disturbances.

A survey is given on congenital and acquired platelet functional disorders. Congenital platelet functional disorders are extremely rare. Acquired platelet functional disorders are probably the most frequent disturbances of haemostasis. The knowledge of the defects leading to inherited platelet function disorders much improved our understanding of platelet function in general. Acquired platelet functional disorders are due to various diseases and drugs.

Platelet function tests are used to detect patients with abnormal platelet function, which may be inborn or acquired or to detect increased platelet activation which may be accompanied by an increased risk of thrombosis. Platelet function tests are also used to monitor platelet function inhibitors as aspirin, clopidogrel or platelet membrane glycoprotein IIb/IIIa-inhibitors. Incorrect blood sampling is a major source of error in measuring platelet function. Global tests besides platelet count and bleeding time are thrombelastography, the platelet function analyzer (PFA) and possibly in the future the new Impact-system. Specific tests measure platelet spreading and adhesion to defined surfaces. In a series of methods platelets are counted before and after passage of a filter. Some of these tests are partially standardized. The most frequently measured platelet function is aggregation induced by ADP, collagen or other substances as first described by Gustav Born. Some newer methods to perform aggregometry are described. Platelet activation can be detected by measuring spontaneous aggregation as in the PAT-test. Prospective trials with this test have shown that enhanced spontaneous aggregation is a risk factor for new vascular occlusions in diabetics and for myocardial infarctions in healthy individuals. The Wu and Hoak-test and the measurement of released platelet factor 4 or betaglobulin are of limited value. Flow cytometric methods are frequently used to measure platelet activation markers as CD 62 and others. Platelet induced thrombin generation is an interesting function to measure drug effects. None of the presently available platelet function tests is well standardized, so there is much room for improvement.

Resistance against the anticoagulatory effect of activated protein C (APC resistance) is the most prevalent hereditary risk factor for venous thromboembolism known today. In this short review, an exemplary casuistic observation from our thrombophilia outpatient ward is presented. The discovery by Dahlbäck et al. in 1993 of hereditary APC resistance as a basis of familial thrombophilia and the molecular characterization of this defect as point mutation in the coagulation factor V gene (FV R506Q- or FV Leiden-mutation) by Bertina and coworkers are discussed. The clinical implications of this thrombophilia and relevant knowledge for daily practice are briefly summarized.

Bleeding symptoms require in many instances immediate professional care. In order to avoid unnecessary treatment, an exact diagnosis is mandatory. In most cases a differentiation between primary humoral and thrombocytogenic bleeding disorders and a secondary bleeding diathesis due to consumption coagulopathy is possible by means of anamnestic, clinical and laboratory parameters. As a single test, the bleeding time gives the best information, followed by the heparin-tolerance-time, the PTT and the platelet count. Withe Quick-test alone, only 5% of children with severe bleeding diathesis are detected. For preoperative laboratory evaluation we recommend a combination of PTT, Quick-test, platelet count and bleeding-time. For the diagnosis of disseminated intravascular coagulation, anamnestic criteria (procoagulant triggers) and clinical evaluation [thrombohemorrhagic syndrome of organ(s)] are as important als laboratory parameters (platelet count, plasminogenproactivator, splits, PTT, Quick-test).

In a retrospective study the results of laboratory investigations were correlated with actual or previous bleeding symptoms of 40 patients. In 22 patients, a defect of hemostasis was documented in the laboratory, whereas the bleeding disorder, suggested by severe hemorrhage, could not be classified in 3 additional patients. In the remaining 15 individuals, no abnormality could be detected by the available laboratory methods. In the group with a documented bleeding disorder, 13 of 22 patients had prolonged bleeding following dental extraction or other surgery of the oral cavity. Other bleeding symptoms were equally distributed among patients with and without a documented defect. 3 patients had a positive family history, i.e. relatives with a hemorrhagic tendency. In 6 patients, a correlation between bleeding and the ingestion of acetylsalicylic acid could be established, while in 4 it was probable. Hemorrhagic complications following oral surgery, particularly in combination with drugs known to interfere with platelet function and a positive family history, strongly suggest an abnormality of hemostasis. Among the 22 patients with a documented defect of hemostasis, only 6 were found who did not present at least one of these leading symptoms.

A thrombocyte counting technique is presented in comparison with the chambre counting according to the German Book of Medicaments (DAB 7 D.L.) GDR on the particle counting device "Laborscale" (PSL-1/PSA-1) of Medicor by using a thrombofuge (70 g). The composition of reagents accounts for problems of measurement which are caused by the device and influences the separation of particles. The possibility of recording the curve of thrombocyte volume distribution and calculating the average thrombocyte volume (VM) is demonstrated by means of a normal collective of test persons as well as by intravascular disorders of haemostasis and during cytostatic therapy.