|Year : 2019 | Volume
| Issue : 4 | Page : 295-301
Sanjay Singh, Neetu Bhari, Rubina Jassi
Department of Dermatology and Venereology, All India Institute of Medical Sciences, New Delhi, India
|Date of Web Publication||30-Sep-2019|
Dr Neetu Bhari
Department of Dermatology and Venereology, All India Institute of Medical Sciences, New Delhi
Source of Support: None, Conflict of Interest: None
Kasabach-Merritt Phenomenon (KMP) is a potentially life-threatening condition characterised by thrombocytopenic consumptive coagulopathy. KMP is almost exclusively associated with two uncommon vascular tumours, Kaposiform haemangioendotheliomas (KHE) and tufted angiomas (TA). It is clinically characterized by a rapid increase in the size of the pre-existing vascular plaque and deranged blood coagulation profiles. Early recognition and treatment is of crucial importance. Hemodynamic stability should be achieved as soon as possible with the use of fresh frozen plasma infusions. Surgical excision and embolization, when feasible, are the line of treatment. Oral prednisolone with or without vincristine are most commonly used and effective treatment. Oral sirolimus has shown its efficacy and safety in recent reports and-series. Propranolol and anti-platelet drugs are commonly used as a second-line therapy. Other drugs and combination therapies are used in non-responsive recalcitrant cases.
Keywords: Kasabach–Merritt phenomenon, thrombocytopenic consumptive coagulopathy, Kaposiform hemangioendothelioma, tufted angioma
|How to cite this article:|
Singh S, Bhari N, Jassi R. Kasabach–Merritt phenomenon. Indian J Paediatr Dermatol 2019;20:295-301
| Introduction|| |
Kasabach–Merritt phenomenon (KMP) is a potentially life-threatening condition characterized by thrombocytopenic consumptive coagulopathy. It was described by Kasabach and Merritt in 1940 in a male with an extensive capillary hemangioma., Although recent studies have shown that KMP is almost exclusively associated with two uncommon vascular tumors, kaposiform hemangioendotheliomas (KHE), and tufted angiomas (TA) which are histologically distinct but related entities and is occasionally seen with angiosarcoma.,, Both are rare tumors and their exact incidence is unknown. Based on the cases observed at a large referral center, the incidence of KHE has been estimated at 0.07/100,000 children per year. It is characterized by severe thrombocytopenia, hypofibrinogenemia, and elevated fibrin degradation products (FDPs) due to ongoing consumptive coagulopathy. About 80% of the cases develop this phenomenon within the 1st year of life with a reported mortality of 10%–37% even after treatment., It shows an unpredictable and variable response to conventional pharmacological drugs, such as vincristine, propranolol, steroids, or interferons. Surgical excision is not feasible in every case. In such circumstances, alternative therapy is needed. Sirolimus has shown promising results although the evidence is available from few case reports and case series only.
Evolution and clinical course of kaposiform hemangioendotheliomas and tufted angiomas
KHE and TA, like infantile hemangiomas, are vascular tumors that present, usually in infancy, as expanding, erythematous, or violaceous soft-tissue masses. KHE is a locally aggressive vascular tumor, commonly presenting in infancy. It generally originates on the skin as a distinctive cutaneous lesion with ill-defined borders, later affecting deeper tissue by infiltrative growth. This lesion occurs most commonly over the extremities and other sites such as the head, neck, trunk, and retroperitoneal or thoracic cavity are rarely involved. Histologically, KHE is composed of infiltrating nodules with slit-like or crescentic vessels that are poorly canalized and lined by spindled endothelial cells. Larger size, deeper involvement, and retroperitoneal location are commonly associated with a higher risk of KMP. All subtypes of KHE are characterized by progressive fibrosis, which carries significant risk for causing long-term morbidity and symptoms.
Tufted angioma is a rare vascular tumor that presents as a solitary, firm, dusky erythematous nodule. It is also called as angioblastoma of Nakagawa. It affects both genders equally. The lesions usually arise between the ages of 1 and 5 years. Occasionally, the lesions may be present at birth. TA usually has a benign course, with only rare reports of aggressive behavior or local invasion. Partial spontaneous regression of TA may occur, but complete disappearance is extremely rare. The most commonly involved sites are neck, upper trunk, and proximal part of extremities. It shows an initial growth phase followed by a static course [Figure 1]. Histopathology is characterized by the vascular tufts of densely packed capillaries, randomly scattered throughout the dermis in a so-called “Cannonball” configuration. There are crescentic spaces surrounding the vascular tufts and lymphatic-like spaces within the tumor stroma [Figure 2].
|Figure 1: Dusky erythematous plaque over the right mandibular area, extending to the right side of neck and chest. A sudden increase in the size, erythema and firmness of the plaque is suggestive of Kasabach-Merritt phenomenon|
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|Figure 2: (a) Hematoxylin and eosin stain (x10) of a punch biopsy showed nodular aggregates in the upper, mid and lower dermis giving a cannonball appearance. (b) Hematoxylin and eosin stain (x40) of a punch biopsy showed these nodular aggregates are composed of proliferating endothelial cell's, capillaries and lymphatics|
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Immunohistochemically, both KHE and TA stains positively for endothelial markers CD31 and CD34. A focal positivity for the lymphatic markers LYVE1, PROX1, and D2-40 is seen. KHE and TA are felt to be a continuum of the same entity and are classified as being of intermediate malignant potential. They are locally aggressive, and adjacent nodal involvement has been reported, but this is now thought to represent multifocal occurrence along a regional lymphatic chain rather than true metastasis. Distant metastasis has not been described. KHE and TA seldom spontaneously regress and tend to progress untreated. After treatment, there is usually a residual lesion, which is smaller in size and may resemble a port-wine stain.
Association with Kasabach–Merritt phenomenon
Croteau et al. in their retrospective study on 107 patients of KHE found 71% of cases associated with KMP. Retroperitoneal and intrathoracic lesions, although less common, were complicated by KMP in 85% and 100% of cases, respectively. Compared with superficial lesions, KHE infiltrating into muscle or deeper was 6.3 fold more likely to manifest KMP and 18-fold higher if retroperitoneal or intrathoracic. Another retrospective review with 19 cases of Kasabach–Merritt phenomenon, KHE was seen in 18 (94.7%) cases and tufted angioma in 1 (5.3%). They need to be differentiated from infantile hemangiomas, as they run a very different clinical course and most frequently require intervention on account of the high mortality rate associated with KMP. Of note, KHE/TA with KMP should be part of the differential diagnosis in any infant presenting with purpura and an unexplained profound thrombocytopenia and coagulopathy, and body cavity imaging should be performed.
| Pathophysiology|| |
The basic pathophysiology of KMP is of platelet trapping, activation, and consumption within the abnormal vascular structure leading to consumption and degradation of fibrinogen, as well as activation and consumption of other coagulation factors. While blood parameters in KMP exhibit similar changes to those seen in disseminated intravascular coagulation (DIC), it should be noted that this is not a disseminated process, but a localized process taking place within the vascular lesion, and should not be referred to as DIC. Platelet activation and aggregation is a self-perpetuating process with adenosine diphosphate (ADP) released from dense bodies of activated platelets, which acts locally to activate more platelets. Prothrombin time (PT) and activated partial thromboplastin time (APTT) are typically prolonged, fibrinogen is reduced, and FDPs and D-dimers are elevated. Localized intralesional bleeding may occur, thus enlarging the lesion and exacerbating the underlying process. A schistocytic hemolytic anemia may also accompany KMP. Mechanical shearing of red blood cells occurs as they are exposed to fibrin clot, and rheological force within the tortuous narrowed and partially thrombosed vasculature of the hemangioendothelioma. Vascular endothelial growth factor released from KHE endothelial cells and platelets lead to further stimulation of angiogenesis. Risk factors for the presence of Kasabach-Merritt syndrome (KMS) include patient age under 6 months, a lesion size of over 5.0 cm, and the existence of a mixed lesion.
| Treatment|| |
There is no well-established strong evidence-based management options for KMP in literature so far because of rare incidence of this phenomenon. There are no randomized controlled trials and prospective studies to evaluate the response of various treatment options. Currently, available treatment options come from case reports and small case series only. Following treatments options are available for managing KMP [Table 1].
|Table 1: Various drugs used in the management of Kasabach-Merritt Phenomenon|
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A patient presenting with KMP should always be assessed for hemodynamic instability. Platelet counts in KMP can be alarmingly low, but clinicians should not be apprehensive as, despite the profound thrombocytopenia, life-threatening hemorrhages are uncommonly seen. Platelet infusion is not recommended unless the patient is actively bleeding or immediately before surgery, because infused platelets have a short circulatory time and may induce a rapid increase in the size of the tumor. Platelet trapping has been demonstrated by tracing transfused radiolabeled platelets trapped inside tumor tissue and by immunohistochemistry which showed positive CD-61., Besides this, radiolabeled fibrinogen has been also found to get trapped locally., Cryoprecipitate or fresh frozen plasma (10–15 mL/kg) can be given in settings of deranged coagulation profile, hypofibrinogenemia whenever there is active bleeding, fibrinogen <1 g ⁄ dL, before surgery, and platelet count <10,000/μL. In case of active bleeding, recombinant human factor VIIa can be used. Despite deranged coagulation parameters including abnormal PT, APTT, and international normalized ratio, use of heparin and low molecular-weight heparin is not recommended in the management of KMP.,
Wide local excision is curative. In 2011, a multidisciplinary expert panel proposed urgent surgical intervention in patients who are hemodynamically unstable or those with threatened limb loss. Although complete surgical resection has been considered as the gold standard in the treatment of KHE, this option is oftentimes associated with an unacceptably high morbidity and mortality. However, only a limited number of cases, surgical interventions is amenable because of lesion infiltration into adjacent structures., Furthermore, anesthesia and surgical interventions in infants and younger child are difficult especially in the setting of altered coagulation profile.
Many agents including platinum thrombogenic microcoils, cellulose porous beads, polyvinyl alcohol particles, and a combination of dexamethasone, bleomycin, and iodinated oil have been used successfully.,, Embolization may not be feasible in tumors that have multiple small feeding vessels. There is a risk of tissue necrosis, and subsequently, pain and pyrexia can develop. Rare complications as limb loss and stroke have also been reported. However, in severe rapidly progressing situation, arterial embolization may serve as a life-saving measure, providing additional time for medical or surgical therapy to be effective as it can have a rapid effect. Ryan et al. in their study on 15 patients of KMP found a partial response in 10 patients. Wang et al. in their study found good response of arterial embolization in 9 out of 14 patients (64%). Combination therapy with vincristine led to the rapid restoration of platelet count in 17 patients of corticosteroid-resistant vascular tumors associated with KMP. Overall, it can be considered as good modality for small or localized lesions and lesions requiring immediate intervention.
Corticosteroids remained one of the mainstay of treatment options of KMP since many years, in spite of the low efficacy and higher probability of relapse when used as monotherapy. In the developing countries, it is still being entertained because of its cost, familiarity with the drug, universal availability, ease of administration, and rapid response. Although the response is relatively rapid and can be seen in days, however, long-term success ranges from 0% to 27%. Prednisolone 2–5 mg/kg is standard dose, but higher doses up to 30 mg/kg have been used. Intravenous methylprednisolone and dexamethasone have also been used. Due to the significant variations in treatment protocols, an expert panel from North America has suggested a uniform approach to treat KHE with KMP, and the group has recommended a combination of systemic corticosteroids and weekly vincristine as the standard of care for KHE associated with KMP., Various side effects such as cushingoid appearance, weight gain, increased risk to infections, hypertension, osteoporosis, and myopathy are important limitations of steroid therapy.
Vincristine is a naturally occurring vinca alkaloid which has been extensively used as a chemotherapeutic drug for lymphoproliferative disorders., It binds to tubulin and interferes with the mitotic spindle microtubules which results in inhibition of the mitosis. In vitro, vincristine also induces apoptosis of tumor cells as well as endothelial cells. It causes minimal bone marrow suppression, but neurotoxicity is the dose-limiting side effect., Other side effects are constipation and syndrome of inappropriate antidiuretic hormone secretion. Various studies have documented strong evidence of vincristine either as monotherapy or in combination with corticosteroids, aspirin, ticlopidine, radiotherapy, and embolization in the management of KMP.,, A meta-analysis has concluded vincristine as considerably more effective with lower complication rates than systemic corticosteroid in the treatment of KHE/TA. Treatment is administered at standard doses (1–1.5 mg/m2 or 0.05–0.065 mg/kg) in weekly intervals through central access and should be continued until a sustained increase in the platelet count has occurred. Average time reported for normalization of the platelet count is 5.3 weeks.
Interferons are uncommonly used due to reported rare serious adverse effect seen in infants as irreversible spastic diplegia., Interferon alpha (IFN-α) should be reserved for immediately life-threatening situations or KMP refractory to multiple treatments. Commonly used regimen is 3 million international units/m2/day. IFN-α2a and 2b has been found to be of equal efficacy., Flu-like symptoms, nausea, fatigue, transient neurological symptoms, liver function derangement, and cytopenia are common adverse effects. Michaud et al. in their meta-analysis found that 11 children out of 441 with vascular lesions receiving interferon therapy developed irreversible spastic diplegia whereas 16 of 441 developed a reversible motor developmental disturbances. Recently, a study has found IFN-α as effective and safe treatment option for refractory KHE and KMP. Twelve patients with KHE received subcutaneous injections of IFN-α at dose of 1 × 106U/m2/day in initial 1st week followed by 3 × 106U/m2/day for 3–9 months. There was reduction in tumor size by >50% in 11 patients and the platelet count returned to normal level in all five patients with KMP.
Propranolol is a nonselective β-adrenergic receptor blocker that has been used widely against various vascular tumors specifically infantile hemangiomas. Various case reports have shown excellent response with propranolol either as monotherapy or as combination therapy.,, However, larger case series have shown discouraging results with only about a third of patients showing response with propranolol monotherapy., Currently, on basis of available evidence, propranolol cannot be considered as a -line therapy for KMP.
Previously, radiation therapy has been widely used for the treatment of infantile hemangiomas and KHEs. A response rate of 75% has been described with the use of radiation in conjunction with steroids with no radiation-induced side effects over a median follow-up of more than 6 years., Due to the risk of secondary malignancies and growth disturbances, radiation therapy can only be used in life-threatening situations or where multiple other safer modalities have failed.
Compression therapy has been used as co-adjunct to various treatment options. It is commonly used over extremities. Mechanisms suggested include decreasing flow in affected limb which subsequently might assist in preventing high output cardiac failure.
Sirolimus, also known as rapamycin, is an inhibitor of the mammalian target of rapamycin (mTOR). It inhibits cell proliferation and metabolism, lymphangiogenesis, and angiogenesis. It has shown to decrease the size of vascular tumors and has resulted in rapid improvement in hematological parameters. Various studies have documented the efficacy of this drug in management of complex vascular anomalies, including KHE.,, Similarly, many authors have found rapid improvement in KMP. Sirolimus is being used for renal transplant in children for many years with good safety margin, however, a risk related to angiogenesis inhibition in the developing infant have been claimed. Recently, a retrospective study with 8 patients of vincristine-resistant KMP have found 100% response in the hematologic parameters at a dose of 0.05 mg/kg/dose, twice daily with a target drug level of 10–15 ng/mL, over a period of 2.9 ± 1.9 weeks. A multicenter, retrospective cohort study on 52 patients of KHE found excellent efficacy of sirolimus and authors have suggested it as a line therapy for the treatment of KHE. In addition, it has been found to be one of the fastest acting medication with an average time to response of 5.3 days. Furthermore, in this study, average time to achieve a sustained platelet count >100 × 109/l was 15.1 days. Only mild side effects as mucositis, grade 1 elevation of transaminases, and thrombocytosis were noted. In animal models, sirolimus has been shown to decrease the fibrosis and this might be a one of the mechanism for sirolimus besides anti-angiogenesis property resulting in regression of KHE which has marked infiltrating tendency to adjacent structures. Overall, sirolimus appears to be a safe and highly effective treatment for this ominous pathology, however, long-term safety is yet to be decided. Recently, a report has found nonresponsiveness of pancreatic KHE associated with KMP with sirolimus.
The role of antiplatelet therapy is controversial in patients with thrombocytopenia; however, there is enough evidence for their use in setting of KMP. Aspirin, dipyridamole, ticlopidine, and pentoxifylline have all been used for KMP either as monotherapy or in combination as dual antiplatelet therapy. Antiplatelet drugs are safe without any increase in bleeding complications. Aspirin and ticlopidine combination is most commonly entertained in practice and dual therapy appears to more efficacious than monotherapy. Aspirin acts by irreversibly inhibiting cyclooxygenase activity leading to inhibition of platelet aggregation while ticlopidine selectively blocks ADP-induced platelet aggregation. Although combination therapy has been found to be effective in many case reports and series, few reports have noted it to be ineffective.
Miscellaneous drugs and treatment options
There are reports of various drugs leading to either complete or partial response in the management of KMP when used as monotherapy or in combination therapy. Isolated reports of everolimus, an mTOR inhibitor, leading to complete remission of KMP exist in literature., Shen et al. used intralesional absolute ethanol every 3 days in eight pediatric patients with KMP at a dose of 0.5–1 ml/kg body weight. Improvement in blood coagulation profile was noted in all the patients after 2 weeks of therapy. After 2 weeks, weekly doses were given. There was no recurrence at 1–3 years of follow-up. Minor complications such as pain, transient bruises, flush on face, local scars, and small areas of local necrosis were noted in this study. Similarly, Yuan et al. have also described good results with intralesional absolute ethanol. Tranexamic acid and aminocaproic acid have been used extensively in KMP previously, usually in combination therapy.,, Combination chemotherapy has been used successfully in the cases resistant to conventional therapies., Fuchimoto et al. successfully treated a child with KHE accompanied by KMP with 4 cycles of combined vincristine, actinomycin D, and cyclophosphamide. Interestingly, multimodal treatments including steroids, interferon-α, radiation, embolization therapy, and vincristine as a monotherapy had failed in this case. Rarely, drugs such as carboplatin, tetrahydropyranyladriamycin, gemcitabine, and vinorelbine have been used in difficult to treat cases.,
Declaration of patient consent
The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.
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Conflicts of interest
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[Figure 1], [Figure 2]